NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells

High aldehyde dehydrogenase (ALDH) activity is a marker commonly used to isolate stem cells, particularly breast cancer stem cells (CSCs). Here, we determined that ALDH1A1 activity is inhibited by acetylation of lysine 353 (K353) and that acetyltransferase P300/CBP-associated factor (PCAF) and deace...

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Bibliographic Details
Published in:The Journal of clinical investigation 2014-12, Vol.124 (12), p.5453-5465
Main Authors: Zhao, Di, Mo, Yan, Li, Meng-Tian, Zou, Shao-Wu, Cheng, Zhou-Li, Sun, Yi-Ping, Xiong, Yue, Guan, Kun-Liang, Lei, Qun-Ying
Format: Article
Language:English
Subjects:
Acetylation
Aldehyde Dehydrogenase - genetics
Aldehyde Dehydrogenase - metabolism
Animals
Biomedical research
Breast cancer
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Dehydrogenases
Development and progression
Diagnosis
Enzymes
Female
Gene expression
Humans
Medical prognosis
Metabolism
Metastasis
Mice
Mice, Inbred NOD
Mice, SCID
Mutation
Neoplasm Proteins - genetics
Neoplasm Proteins - metabolism
Neoplastic Stem Cells - metabolism
Neoplastic Stem Cells - pathology
Oxidoreductases
p300-CBP Transcription Factors - genetics
p300-CBP Transcription Factors - metabolism
Peptides
Physiological aspects
Receptors, Notch - genetics
Receptors, Notch - metabolism
Signal Transduction
Sirtuin 2 - genetics
Sirtuin 2 - metabolism
Stem cells
Studies
Tumorigenesis
Tumors
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Summary:High aldehyde dehydrogenase (ALDH) activity is a marker commonly used to isolate stem cells, particularly breast cancer stem cells (CSCs). Here, we determined that ALDH1A1 activity is inhibited by acetylation of lysine 353 (K353) and that acetyltransferase P300/CBP-associated factor (PCAF) and deacetylase sirtuin 2 (SIRT2) are responsible for regulating the acetylation state of ALDH1A1 K353. Evaluation of breast carcinoma tissues from patients revealed that cells with high ALDH1 activity have low ALDH1A1 acetylation and are capable of self-renewal. Acetylation of ALDH1A1 inhibited both the stem cell population and self-renewal properties in breast cancer. Moreover, NOTCH signaling activated ALDH1A1 through the induction of SIRT2, leading to ALDH1A1 deacetylation and enzymatic activation to promote breast CSCs. In breast cancer xenograft models, replacement of endogenous ALDH1A1 with an acetylation mimetic mutant inhibited tumorigenesis and tumor growth. Together, the results from our study reveal a function and mechanism of ALDH1A1 acetylation in regulating breast CSCs.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI76611